Optically active poly (N-methylbenzylmaleimide), method for its production and its use

ABSTRACT

An optically active poly(N-α-methylbenzylmaleimide) represented by the following formula (1):  
                 
 
     wherein n is a number within a range of from 2 to 10,000, and symbol * represents optically active carbon, and having a specific rotation ([α] 435   25 ) of at least +30°.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a novel optically activepolymaleimide derivative and a method for its production. The opticallyactive polymaleimide derivative is expected to be useful for e.g. aseparating medium.

[0003] 2. Discussion of Background

[0004] It is known that an optically active polymaleimide polymer havinga certain degree of specific rotation, can be produced by radicalpolymerization or anionic polymerization using optically active(R)-(+)-N-α-methylbenzylmaleimide as the starting material (T. Oishi etal., J. Polym. Chem. Ed., 22, 2789-2800 (1984)).

[0005] On the other hand, a method for obtaining an optically activepolymaleimide derivative by asymmetric anionic polymerization of anachiral maleimide derivative, is also known (T. Oishi et al., ChemistryLetters, 1998, 791-792).

[0006] However, by the radical polymerization method using opticallyactive (R)-(+)-N-α-methylbenzylmaleimide as the starting material andemploying azoisobutyronitrile, the product obtained is of such a lowlevel that the specific rotation ([α]₄₃₅ ²⁵) is not more than +30°, andthe number average molecular weight (Mn) as calculated as standardpolystyrene is up to about 3,000.

[0007] Further, also by the anionic polymerization using the samestarting material and employing butyl lithium, the product obtained isof such a level that the specific rotation is from 0 to −100°, and themolecular weight (Mn) is not more than 3×10³. Thus, optically activepolymaleimide derivatives obtained by these conventional methods werenot satisfactory with respect to both optical purities and molecularweights, when application to e.g. a separating medium, was taken intoaccount.

[0008] On the other hand, by the method for obtaining an opticallyactive polymaleimide derivative by asymmetric anionic polymerizationusing an achiral maleimide derivative, it is possible to obtain anoptically active polymer having a certain degree of specific rotation,but the molecular weight is as low as about 1×10³. Further, no case isknown wherein the same method is applied by using an optically activemaleimide derivative as a starting material.

SUMMARY OF THE INVENTION

[0009] The present inventors have conducted an extensive study todevelop an optically active poly(N-α-methylbenzylmaleimide) having ahigher optical purity and molear weight, and as a result, have found itpossible to oin an optically active poly(N-α-methylbenzylmaleimide)having a high specific rotation and a high molecular weight by usingoptically active (S)-(−)-N-α-methylbenzylmaleimide as the startingmaterial and carrying out anionic polymerization in the presence of anasymmetric ligand. The present invention has been accomplished on thebasis of this discovery.

[0010] Namely, the present invention provides an optically active poly(N-α-methylbenzylmaleimide) represented by the following formula (1):

[0011] wherein n is a number within a range of from 2 to 10,000, andsymbol * represents optically active carbon, and having a specificrotation ([α]₄₃₅ ²⁵) of at least +30°.

[0012] Further, the present invention provides a method for producingthe above-mentioned optically active poly(N-α-methylbenzylmaleimide),which comprises subjecting (S)-(−)-N-α-methylbenzylmaleimide of thefollowing formula (2):

[0013] to anionic polymerization in the presence of an asymmetricligand.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 is a measurement chart showing the results of Example 8.

[0015]FIG. 2 is a measurement chart showing the results of Example 9.

[0016]FIG. 3 is a measurement chart showing the results of Example 10.

[0017]FIG. 4 is a measurement chart showing the results of Example 11.

[0018]FIG. 5 is a measurement chart showing the results of Example 8(upper chart: measurement by an optical rotation detector; lower chart:measurement by a UV detector)

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Now, the present invention will be described in detail.

[0020] The optically active poly(N-α-methylbenzylmaleimide) of thepresent invention is a compound which is represented by the aboveformula (1) and which has a specific rotation ([α]₄₃₅ ²⁵) of at least+30°, and its number average molecular weight (Mn) is usually at least3×10³ as calculated as standard polystyrene.

[0021] The optically active poly(N-α-methylbenzylmaleimide) of thepresent invention can be obtained by subjecting(S)-(−)N-α-methylbenzylmaleimide of the above formula (2) to anionicpolymerization in the presence of an asymmetric ligand.

[0022] In the method of the present invention, the(S)-(−)-N-α-methylbenzylmaleimide to be used as the starting material,can be easily prepared by reacting optically active(S)-(−)-methylbenzylamine[(S)-(−)-1-phenylethylamine] with maleicanhydride by a known method. The specific rotation ([α]₄₃₅ ²⁵) of theobtainable (S)-(−)-N-α-methylbenzylmaleimide can be brought to a levelof −98.1° by repeating purification by distillation.

[0023] In the method of the present invention, the asymmetric ligand andan anionic polymerization catalyst are added to a solvent for thereaction, and then the starting material(S)-(−)-N-α-methylbenzylmaleimide is added thereto and reacted.

[0024] In the method of the present invention, the anionicpolymerization catalyst may, for example, be an organic metal catalystsuch as n-butyl lithium, fluorenyl lithium, diethylzinc or dimethylzinc,as a suitable one. It is used usually within a range of from 0.1 to 30mol %, based on the starting material (S)-(−)-N-α-methylbenzylmaleimideto be subjected to the reaction.

[0025] In the method of the present invention, the optically activeligand to be used for the anionic polymerization, may, for exmpale, be(−)-sparteine (hereinafter referred to as Sp) of the following formula(3):

[0026] or(4S)-2,2′-(1-ethylpropylidene)bis[4-(1-phenylethyl)-4,5-dihydroxazole](hereinafter referred to simply as Bnbox) of the following formula (4):

[0027] as a suitable one. The optically active ligand is usedtheoretically in an equimolar amount to the anionic polymerizationcatalyst to be used for the reaction, but it is used preferably in anamount of from 1.02 to 1.5 mols, to carry out the reaction under astabilized condition.

[0028] The solvent for the reaction useful for the method of the presentinvention, is not particularly limited, and any solvent can be used solong as it is inert to the reaction. Specifically, an ether-type solventsuch as diethyl ether, di-n-propyl ether, di-i-propyl ether, di-n-butylether, di-t-butyl ether or tetrahydrofuran (hereinafter referred tosimply as THF), or an aromatic hydrocarbon type solvent such as benzene,toluene, xylene, ethylbenzene or mesitylene, may, for example, bementioned as a suitable one.

[0029] In the method of the present invention, the amount of the solventis not particularly limited, and it is used usually in an amount of from2 to 100 times by weight, relative to the(S)-(−)-N-α-methylbenzylmaleimide to be subjected to the reaction. Inthe method of the present invention, the reaction temperature variesdepending upon the reaction condition and is not particularly limited,but the reaction is usually carried out in a range of −78° C. to 100° C.

[0030] In the method of the present invention, the reaction time variesdepending upon the catalyst and the reaction temperature and is notparticularly limited, but the reaction is usually completed within arange of from 1 to 240 hours.

[0031] After completion of the reaction, the reaction solution isdropwise added to a solvent having a low solubility of the product, suchas hexane, heptane, methanol, ethanol or isopropanol, forcrystallization, whereby the optically active polymaleimide derivativeof the present invention can be obtained in the form of a powder. Inorder to improve the purity, it may be dissolved again in a solvent suchas THF or toluene, and then put into e.g. methanol again forrecrystallization.

[0032] A separating medium made of the optically active polymaleimidederivative of the present invention, contains the compound of the aboveformula (1) as the effective component.

[0033] As the optically active polymaleimide derivative of the aboveformula (1) as the effective component of the separating medium of thepresent invention, any derivative may be used so long as it is a polymerhaving a specific rotation ([α]₄₃₅ ²⁵) of at least +30°, which isobtained by subjecting the optically active maleimide derivative of theabove formula (2) to anionic polymerization in the presence of anasymmetric ligand, as mentioned above.

[0034] The separating medium comprising the optically activepolymaleimide derivative of the above formula (1) of the presentinvention, can be used widely as an agent for optical resolution of anoptically active compound. A method for-optical resolution of anoptically active compound by means of the separating medium of thepresent invention, is not particularly limited. However, for example, anoptically active substance can easily be separated by a chromatographymethod such as gas chromatography, high performance liquidchromatography or thin layer chromatography.

[0035] When the separating medium of the present invention is used as astationary phase of a column packing material for high performanceliquid chromatography, the eluent is not particularly limited except fora liquid which dissolves the separating medium of the present inventionor which reacts therewith. The separating medium of the presentinvention is useful for either a normal phase liquid chromatographyemploying e.g. hexane/isopropanol or a reversed phase liquidchromatography employing e.g. an alcohol/water.

[0036] In the present invention, the optically active polymaleimidederivative of the above formula (1) may be used by itself as aseparating medium, but for the purpose of improving the pressureresistance of the separating medium, prevention of swelling or shrinkagedue to substitution by a solvent or improvement of the theoretical platenumber, it may be supported on some carrier.

[0037] As the carrier, a porous carrier such as silica gel, alumina,crosslinked polystyrene or polysiloxane, may, for example, be mentionedas a suitable one, and surface treatment may be applied by using anorganic silane compound in order to improve the affinity to theoptically active polymaleimide derivative.

[0038] The particle size of the carrier varies depending upon the columnto be used or the size of the plates and is not particularly limited,but it is usually from 1 μm to 10 mm, preferably from 1 to 300 μm.Further, the average pore diameter is usually from 10 Å to 100 μm,preferably from 50 to 100,000 Å. When used as a stationary phase of acolumn packing material for a high performance liquid chromatography,the carrier is preferably a porous carrier having a particle size offrom 1 to 200 μm and an average pore diameter within a range of from 10to 3000 Å.

[0039] The method to have the optically active polymaleimide derivativesupported on the carrier may be a physical method or a chemical methodand is not particularly limited. The physical method may, for example,be a method wherein the optically active polymaleimide derivative andthe porous carrier are contacted each other. The chemical method may,for example, be a method wherein a functional group is imparted to theterminal of the polymer at the time of preparing the optically activepolymaleimide derivative, and it is chemically bonded to the porouscarrier.

[0040] The amount of the optically active polymaleimide derivative to besupported on the carrier varies depending upon the type and the physicalproperties of the carrier to be used and is not particularly limited,but it is usually within a range of from 1 to 100 wt %, based on theweight of the carrier.

[0041] The separating medium of the present invention is useful not onlyfor the packing material of a high performance liquid chromatographycolumn, but also as a shifting reagent for a nuclear magnetic resonancespectrum (NMR), or as a supported material for a column for opticalresolution by gas chromatography.

[0042] According to the present invention, a novel optically activepoly(N-α-methylbenzylmaleimide) having a high (+) rotatory power, whichis expected to be useful for e.g. a separating medium for an opticallyactive compound, can be provided by a simple production method. Theseparating medium made of the optically active compound of the presentinvention is applicable to various types of separation, and it isindustrially very significant.

[0043] Now, the present invention will be described in further detailwith reference to Examples. However, it should be understood that thepresent invention is by no means restricted to such specific Examples.

[0044] The optically active ligand, i.e.(4S)-2,2′-(1-ethylpropylidene)bis[4-(1-phenylethyl)-4,5-dihydroxazole](Bnbox),to be used in-the preparation of the optically active polymaleimidederivative of the present invention, is one prepared by the methoddisclosed in S. E. Denmark, et al., J. Org. Chem., 60, 4884 (1995).

[0045] The average molecular weight was calculated as a standardpolystyrene by gel permeation chromatography (high performance GPCsystem, manufactured by TOSOH CORPORATION), and the specific rotationwas measured by DIP-181, manufactured by JASCO.

[0046] For the measurement of the resolution power of the preparedoptically active polymaleimide derivative, a multipump CCPM,manufactured by TOSOH CORPORATION, an ultraviolet detector UV-8020 andan integrator of CHROMATOCORDER 21, were employed.

REFERENCE EXAMPLE 1

[0047] Preparation of (S)-(−)-N-α-methylbenzylmaleimide

[0048] The preparation was carried out in accordance with the methoddisclosed in P. Y. Reddy, et al., J. Org. Chem., 62, 2652 (1997).

[0049] Into a 500 ml round bottomed three necked flask equipped with acondenser, a dropping funnel and a stirrer, 4.0 g (40.8 mmol) of maleicanhydride and 240 ml of dry benzene were put and dissolved withstirring, and then cooled to 0° C. on an ice bath.

[0050] Then, a solution prepared by dissolving 5.2 ml (40.8 mmol) of(S)-(−)-1-phenylethylamine in 100 ml of dry benzene, was added theretoby means of the dropping funnel, and then the mixture was returned toroom temperature and stirred for one hour.

[0051] Further, while stirring the reaction solution vigorously, 5.56 g(40.8 mmol) of zinc chloride was added thereto, and the mixture washeated to 80° C. on an oil bath, whereupon a solution prepared bydissolving 11.5 ml (54.5 mmol) of hexamethyldisilazane in 80 ml of drybenzene, was dropwise added by means of the dropping funnel, and thereaction was carried out further for 5 hours under reflux by heating.

[0052] After completion of the reaction, the reaction mixture was cooledto room temperature, washed with 0.5 N hydrochloric acid and extractedwith ethyl acetate, and the extract was washed with a saturated sodiumhydrogencarbonate aqueous solution and then with a saturated sodiumchloride aqueous solution, and dried over anhydrous magnesium sulfateand concentrated to obtain crude (S)-(−)-N-α-methylbenzylmaleimide. Theobtained crude (S)-(−)-N-α-methylbenzylmaleimide was then purified bycolumn chromatography (n-hexane/ethyl acetate=4/1, vol/vol) and thenpurified by distillation (114° C./8.3×10⁻³ mmHg), to obtain 6.9 g of awhite solid (yield: 84%).

[0053] Melting point (0° C.): 33 to 35° C.

[0054] Specific rotation ([α]₄₃₅ ²⁵): −98.1° (C=1.0, THF)

EXAMPLE 1

[0055] Into a 25 ml eggplant type flask containing a magnetic stirrer,30.9 mg (0.25 mmol) of diethylzinc, 70.3 mg (0.30 mmol) of (−)-sparteineand 5 ml of toluene were charged and stirred at 0° C. for 30 minutes,whereupon 503 mg (2.50 mmol) of (S)-(−)-N-α-methylbenzylmaleimideobtained in Reference Example 1, was added, and a reaction was carriedout further at the same temperature for 72 hours.

[0056] After completion of the reaction, the reaction solution was putinto 50 ml of methanol, and then, the precipitated product was collectedby filtration and dried under reduced pressure at room temperature toobtain 0.5 g of the desired optically activepoly(N-α-methylbenzylmaleimide) as slightly yellow powder (yield: 100%)

[0057] Number average molecular weight (Mn)=12.7×10³, Mw/Mn=10.0

[0058] Specific rotation ([α]₄₃₅ ²⁵)=242.2° (C=1.0, CHCl₃)

[0059] [Specific rotation [α]₄₃₅ ²⁵ of THF soluble content=206.0°(C=1.0, THF)]

EXAMPLES 2 and 3

[0060] Using the same reaction apparatus as in Example 1, the reactionwas carried out under the conditions shown in Table 1. The results areshown in Table 1. with respect to the conditions not shown in Table 1,the reaction was carried out under the same conditions as in Example 1.

EXAMPLES 4 to 6

[0061] Using the same reaction apparatus as in Example 1, the reactionwas carried out under the conditions shown in Table 1. The results areshown in Table 1. With respect to the conditions not shown in Table 1,the reaction was carried out under the same conditions as in Example 1.TABLE 1 Amount of Reaction Reaction Molecular³⁾ Optical⁵⁾ catalysttemperature time Yield²⁾ weight: Mn rotation Catalst¹⁾ (mol %) Solvent(° C.) (hrs) (%) (× 10³) Mw/Mn⁴⁾ (°) Ex. 2 (1) 10 Toluene −35 72 14.810.5 13.4 +346.9⁶⁾ Ex. 3 (1) 10 Toluene −35 44 80.5 —⁴⁾ —⁴⁾ +466.2⁶⁾ Ex.4 (2) 10 THF 0 72 100 8.9 2.4 +36.1 Ex. 5 (2) 10 Toluene rt 72 100 10.92.9 +36.5 Ex. 6 (2) 10 THF rt 72 100 27.2 2.5 +39.5 Comp Ex. 1 (3) 5Toluene 60 24 88.1 3.0 1.9 −30.1 Comp Ex. 2 (4) 10 Toluene 0 24 58.9 3.11.6 −94.5 Comp Ex. 3 (5) 10 Toluene rt 120 61.4 3.1 1.4 −106.9

COMPARATIVE EXAMPLES 1 to 3

[0062] Using the same reaction apparatus as in Example 1, the reactionwas carried out under the conditions shown in Table 1. The results areshown in Table 1. With respect to the conditions not shown in Table 1,the reaction was carried out under the same conditions as in Example 1.

EXAMPLE 7

[0063] Preparation of silica gel supporting 10% of optically activepoly(N-α-methylbenzylmaleimide) (specific rotation [α]₄₃₅ ²⁵=206.0°(C=1.0, THF)) and a column packed therewith.

[0064] Into a 50 ml eggplant type flask, 500 mg of the optically activepoly(N-α-methylbenzylmaleimide) (specific rotation [α]₄₃₅ ²⁵=206.0°(C=1.0, THF)) prepared in Example 1, and 10 ml of chloroform, werecharged and dissolved, whereupon 4.5 g of silica gel (average particlesize: 10 μm, average pore diameter 100 Å) was added, and then chloroformwas distilled off under reduced pressure by a rotary evaporator toobtain 5 g of silica gel supporting 10% of the desired optically activepoly(N-α-methylbenzylmaleimide) (specific rotation [α]₄₃₅ ²⁵=206.0°(C=1.0, THF)).

[0065] The obtained silica gel supporting 10% of the optically activepoly(N-α-methylbenzylmaleimide) (specific rotation [α]₄₃₅ ²⁵=206.0°(C=1.0, THF)), was dispersed in methanol and then packed into astainless steel column of 2 mmID×150 mmL by means of a high pressurepump at a flow rate of 3.5 ml/min under the highest pressure of 400kg/cm². The theoretical plate number of the obtained column was 743plates. For the measurement of the theoretical plate number, methanolwas used as an eluent, and the theoretical plate number was measured byelution of toluene. The theoretical plate number was calculated by thefollowing formula.

Theoretical plate number (N)=5.54×[Tr/W_(1/2)]]²

[0066] Tr=retention time (sec)

[0067] W_(1/2)=half value width (mm)

EXAMPLES 8 to 11

[0068] Using the column prepared in Example 7, separation of variouscompounds was carried out under the conditions shown in Table 2. Theresults are also shown in Table 2, and their measurement charts are alsoshown in FIGS. 1 to 4. TABLE 2 Mobile Flow rate Measurement ExampleCompound¹⁾ phase²⁾ ml/min k1′³⁾ k2′⁴⁾ α⁵⁾ chart 8 A (1) 0.5 5.1 6.5 1.279 A (1) 0.1 5.2 7.3 1.39 10 B (1) 0.5 26.1 29.8 1.14 11 C (1) 0.3 5.05.9 1.20

[0069] Further, in order to confirm the optical resolution in Example 8,an ultraviolet detector and an optical rotation detector were connectedin parallel, and the measurements were carried out. The results areshown in FIG. 5 (upper chart: optical rotation detector, lower chart: UVdetector). By the optical rotation detector, the optical resolution of aracemic modification was confirmed.

COMPARATIVE EXAMPLE 4

[0070] Into a 25 ml eggplant type flask containing a magnet stirrer, 4.1mg (0.025 mmol) of 2,2-azobis(isobutylnitrile) and 5 ml of toluene werecharged and stirred at room temperature for 30 minutes, whereupon 503 mg(2.50 mmol) of (S)-(−)-N-α-methylbenzylmaleimide obtained in ReferenceExample 1, was added. Then, the mixture was heated on an oil bath, andthe reaction was carried out at 50° C. for 24 hours.

[0071] After completion of the reaction, the reaction solution was putinto 50 ml of methanol, and then, the precipitate was collected byfiltration and dried under reduced pressure at room temperature toobtain 0.5 g of poly(N-α-methylbenzylmaleimide) formed by radicalpolymerization, as slightly yellow powder (yield: 100%).

[0072] Number average molecular weight (Mn)=6.0×10³, Mw/Mn=31.6

[0073] Specific rotation [α]₄₃₅ ²⁵=−123.5° (C=1.0, CHCl₃)

COMPARATIVE EXAMPLE 5

[0074] A packing material having 10% of the polymaleimide obtained inComparative Example 4, supported on silica gel in the same manner as inExample 7, was prepared, and (±)-2,3-dihydro-2-benzyloxy)-4H-pyran-4-onewas analyzed under the same condition as in Example 8, whereby a singlepeak was observed, and no resolution was observed.

[0075] The entire disclosure of Japanese Patent Application No.2000-295454 filed on Sep. 25, 2000 including specification, claims,drawings and summary are incorporated herein by reference in itsentirety.

What is claimed is:
 1. An optically activepoly(N-α-methylbenzylmaleimide) represented by the following formula(1):

wherein n is a number within a range of from 2 to 10,000, and symbol *represents optically active carbon, and having a specific rotation([α]₄₃₅ ²⁵) of at least +30°.
 2. A method for producing an opticallyactive poly(N-α-methylbenzylmaleimide) as defined in claim 1, whichcomprises subjecting (S)-(−)-N-α-methylbenzylmaleimide of the followingformula (2):

to anionic polymerization in the presence of an asymmetric ligand. 3.The method for producing an optically activepoly(N-α-methylbenzylmaleimide) according to claim 2, wherein theasymmetric ligand is a compound of the formula (3) or (4):


4. A separating medium containing an optically activepoly(N-α-methylbenzylmaleimide) represented by the following formula(1):

wherein n is a number within a range of from 2 to 10,000, and symbol *represents optically active carbon, and having a specific rotation([α]₄₃₅ ²⁵) of at least +30°.
 5. A separating medium having supported ona carrier an optically active poly(N-α-methylbenzylmaleimide)represented by the following formula (1):

wherein n is a number within a range of from 2 to 10,000, and symbol *represents optically active carbon, and having a specific rotation([α]₄₃₅ ²⁵) of at least +30°.
 6. A method for separating an opticallyactive compound, which comprises separating an optically active compoundby chromatography employing the separating medium as defined in claim 4.7. A method for separating an optically active compound, which comprisesseparating an optically active compound by chromatography employing theseparating medium as defined in claim
 5. 8. A packing material for ahigh performance liquid chromatography column, which contains, as astationary phase component, the separating medium as defined in claim 4.9. A packing material for a high performance liquid chromatographycolumn, which contains, as a stationary phase component, the separatingmedium as defined in claim 5.